Hippocampal Extracellular Signal-regulated Kinase Research Articles

The memory modulatory effect of agmatine in passive avoidance task coincides with alterations of hippocampal CaMKII-α and ERK signaling in mice

Agmatine is a polyamine suggested to act as a supposed neurotransmitter in the brain. Evidence has indicated that acute agmatine administration might modulate memory. The present study aimed to investigate the effect of repeated agmatine treatment on passive avoidance memory, hippocampal calcium–calmodulin-dependent protein kinase II-alpha (CaMKII-α), and Extracellular Signal-Regulated Kinase (ERK) signaling pathways in naive mice. Adult male NMRI mice were treated with agmatine (10, 20, 30, 40, and 80 mg/kg/ip) or saline for 11 days. Acquisition and retention tests of passive avoidance memory were performed on days 10 and 11, respectively. Following the memory retention test, the hippocampi were assessed for the levels of CaMKII-α and ERK using the western blotting technique. The results revealed the dose-dependent effect of agmatine on the passive avoidance memory. Accordingly, the memory was impaired in lower doses, but was improved in higher ones. Agmatine in none of the doses affected the nociception of the mice in tail-flick test. Furthermore, agmatine increased the phosphorylation of CaMKII-α and ERK in the hippocampus at memory enhancing doses, while ERK phosphorylation decreased following the impairing doses of agmatine. Thus, the dose-dependent effect of agmatine on memory might be related to its modulatory effect on CaMKII-α and ERK signal transduction, eventually regulating the memory process.

Effects of sub-chronic caffeine ingestion on memory and the hippocampal Akt, GSK-3β and ERK signaling in mice

Caffeine, one of the most widely consumed psychoactive substance in the world, has been shown to affect mood, memory, alertness, and cognitive performance. This study aimed to assess the effect of sub-chronic oral gavage of caffeine on memory and the phosphorylation levels of hippocampal Akt (protein kinase B), GSK-3β (Glycogen Synthase Kinase-3beta) and ERK (extracellular signal-regulated kinase) in mice. Adult male NMRI mice were administered with caffeine at the doses of 0.25, 0.5, 0.75 and 1.5 mg/kg/oral gavage for 10 days before behavioral assessments. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of Akt, GSK-3β and ERK proteins. The results showed that sub-chronic caffeine ingestion at the dose of 0.5 mg/kg improves memory in mice both in passive avoidance and novel object recognition tasks. Furthermore, this memory enhancing dose of caffeine elevated the ratios of phosphorylated to total contents of hippocampal Akt, GSK-3β and ERK. This study suggests that sub-chronic low dose of caffeine improves memory and increases the phosphorylation of hippocampal Akt, GSK-3β and ERK proteins.

Effects of sub‐chronic oral caffeine consumption on memory and the hippocampal Akt, GSK‐3β and ERK in mice

AbstractBackgroundCaffeine, one of the most widely consumed psychoactive substance in the world, has been shown to affect mood, memory, alertness, and cognitive performance. However, the literature about the effects of caffeine intake on memory is equivocal. This study aimed to assess the effect of sub‐chronic oral gavage of caffeine on memory and the phosphorylation levels of hippocampal Akt (protein kinase B), GSK‐3β (Glycogen Synthase Kinase‐3beta) and ERK (extracellular signal‐regulated kinase) in mice.MethodAdult male NMRI mice were administered with sub‐chronic caffeine at the doses of 0.25, 0.5, 0.75 and 1.5 mg/kg/oral gavage for 10 days before training which continued until the retention day of passive avoidance task. Upon completion of the behavioral assessments, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of Akt, GSK‐3β and ERK proteins.ResultThe results showed that sub‐chronic caffeine ingestion at the dose of 0.5 mg/kg improves memory in mice. Furthermore, the memory enhancing dose of caffeine (0.5 mg/kg) elevated the phosphorylated to total ratios of hippocampal Akt, GSK‐3β and ERK.ConclusionThis study suggests that sub‐chronic low dose of caffeine improves memory and increases the phosphorylation of hippocampal Akt, GSK‐3β and ERK proteins.

Prenatal exposure to methadone or buprenorphine alters µ-opioid receptor binding and downstream signaling in the rat brain.

There is a growing concern related to the use of opioid maintenance treatment during pregnancy. Studies in both humans and animals have reported reduced cognitive functioning in offspring prenatally exposed to methadone or buprenorphine; however, little is known about the neurobiological mechanisms underlying these impairments. To reveal possible neurobiological effects of such in utero exposure, we examined brain tissue from methadone- and buprenorphine-exposed rat offspring previously shown to display impaired learning and memory. We studied µ-opioid receptor (MOR) and N-methyl-D-aspartate receptor (NMDAR) binding in the rat offspring cerebrum during development and in the hippocampus at young adulthood. Moreover, we examined activation of the Ca2+ /calmodulin-dependent protein kinase II (CaMKII) and the extracellular signal-regulated kinase (ERK), which are central in the downstream signaling of these receptors. The methadone- and buprenorphine-exposed rat pups displayed reduced MOR binding up to two weeks after birth, whereas the NMDAR binding was unaffected. Prenatal exposure to methadone or buprenorphine also resulted in decreased activation of CaMKII and/or ERK during development, while young adult offspring displayed increased hippocampal ERK activation. In conclusion, our findings suggest that prenatal exposure to exogenous opioids, such as methadone or buprenorphine, may disturb the endogenous opioid system during development, with long-term effects on proteins important for cognitive functioning.

The rostral ventromedial medulla orexin 1 receptors and extracellular signal-regulated kinase in hippocampus are involved in modulation of anxiety behavior induced by dental pulp nociception in adult male rats

ObjectivesTo explore the role of rostral ventromedial medulla (RVM) orexin 1 receptors (OX1R) on orofacial nociception -induced anxiety and locomotion in rats. DesignForty two adult male Wistar rats (220–270 gr) were randomly divided into 7 groups (n = 6) as follows: untreated control, capsaicin, capsaicin vehicle-treated group (sham operation), capsaicin groups pretreated by intra-RVM administration orexin 1 receptor (OX1R) agonist (orexin A) or antagonist (SB-334867) and the capsaicin groups treated by drugs vehicles (DMSO or aCSF). Orofacial nociception was induced by intradental application of capsaicin (100 μg) into the incisors of rats. Anxiety level and locomotor activity were measured by the elevated plus maze (EPM) and open field (OF) tests, respectively. Hippocampal levels of phosphorylated extracellular signal regulated Kinase (p-ERK) was also assessed by western blotting. ResultsIntradental application of capsaicin significantly increased anxiety and decreased locomotion behaviors. Intra-RVM microinjection of orexin-A significantly prevented capsaicin-induced anxiety-like behavior and increased locomotor activity in the EPM and OF tests. These effects were inhibited by SB-334867. Furthermore, orexin-A significantly increased p-ERK levels in capsaicin-treated rats. This effect was inhibited by pretreatment of the rats with SB-334867. ConclusionsThe results suggest that both OX1R signaling in the RVM and hippocampal p-ERK signaling are involved in orofacial nociception-induced anxiety as well as locomotor activity.

The effect of cinnamaldehyde on passive avoidance memory and hippocampal Akt, ERK and GSK-3β in mice

Cinnamon, a spice widely used in cuisine, has been reported to exert therapeutic effects. Recently, cinnamon was shown to improve memory in some animal models of memory impairment and in poor learning mice. This study aimed to investigate the effect of cinnamaldehyde, the major compound in cinnamon on passive avoidance memory and activation of hippocampal Akt (protein kinase B), ERK (extracellular signal-regulated kinase) and GSK-3β (Glycogen Synthase Kinase-3beta) in mice. In the present study, oral cinnamaldehyde at doses of 12.5, 25, 30, 40, 45, 50 and 100 mg/kg/daily was administered to adult male NMRI mice, initiated 10 days before training and continued during training and retention days. Training of passive avoidance task was performed on day 10 and a retention trial was done 24 h after. Upon completion of the retention test, hippocampi were removed for Western blot analysis to detect the phosphorylated and total levels of Akt, ERK and GSK-3β proteins. Results showed that cinnamaldehyde exerts a biphasic effect on passive avoidance memory by impairing memory at lower doses while improving at higher doses. Moreover, at memory improving doses, cinnamaldehyde increased the phosphorylated forms of hippocampal Akt, ERK and GSK-3β while these proteins did not change at impairing doses of cinnamaldehyde. For the first time, this study revealed a biphasic effect of cinnamaldehyde on memory as well as indicating that the memory improving effect of higher doses of this substance is accompanied with hippocampal Akt, ERK and GSK-3β signaling alterations in adult mice.

Upregulation of hippocampal extracellular signal-regulated kinase (ERK)-2 induces antidepressant-like behavior in the rat forced swim test.

The hippocampus mediates responses to affect-related behavior in preclinical models of pharmacological antidepressant efficacy, such as the forced swim test. However, the molecular mechanisms that regulate escape-directed behavior in this preclinical model of despair are not well understood. Here, using viral-mediated gene transfer, we assessed how overexpression of extracellular signal-regulated protein kinase (ERK)-2 within the dorsal hippocampus influenced behavioral reactivity to inescapable swimming stress in adult male Sprague-Dawley rats. When compared to controls, rats overexpressing hippocampal ERK-2 displayed increases in the time to initially adopt a posture of immobility, along with decreases in total time spent immobile, without influencing general locomotor activity. Collectively, the results indicate that hippocampal upregulation of ERK-2 increases escape-directed behavior in the rat forced swim test, thus providing insight into the neurobiological mechanisms that mediate antidepressant efficacy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Role of hippocampal ERK1/2 in exogenous carbon monoxide-induced improvement of cognitive function in a rat model of hemorrhage shock and resuscitation

Objective To evaluate the role of hippocampal extracellular signal-regulated kinase 1/2 (ERK1/2) in exogenous carbon monoxide(CO)-induced improvement of cognitive function in a rat model of hemorrhage shock and resuscitation. Methods Ninety clean-grade healthy male Sprague-Dawley rats, aged 9-10 weeks, weighing 350-400 g, were divided into 5 groups (n=18 each) using a random number table method: sham operation group (S group), hemorrhage shock and resuscitation group (H group), CO group, PD98059-CO group (PCO group) and PD98059 group (P group). Hemorrhagic shock was induced by withdrawing blood from the femoral vein until mean arterial pressure was reduced to 25-35 mmHg which was maintained for 60 min and resuscitated by infusing the blood withdrawn over 15 min until the initial blood pressure was achieved, and normal saline was infused when needed.Rats were exposed to air mixture containing 1% CO for 3 h in a glass box after the end of resuscitation in group CO.ERK1/2 inhibitor PD98059 (30 μmol/L) 30 μl was injected into the cerebral ventricle at 30 min before hemorrhage in PCO and PC groups.Right femoral artery and vein were only cannulated, and normal saline was injected into the cerebral ventricle in group S. Rats were sacrificed at 3 h after the end of resuscitation, brains were removed and hippocampi were isolated for determination of CO content (by gas chromatograph assay). Cognitive function was assessed by Morris water maze test at 15 days after the end of resuscitation, rats were then sacrificed and hippocampi were isolated for determination of cell apoptosis in hippocampal CA1 region by TUNEL and cleaved caspase-3 immunofluorescence, and the apoptosis rate was calculated.Rats were sacrificed at 6 h after the end of resuscitation, and hippocampi were isolated to detect the expression of phosphorylated ERK1/2 (p-ERK1/2), Bcl-2 and Bax by Western blot. Results Compared with group S, the escape latency was significantly prolonged in H, PCO and P groups, and the hippocampal CO content and apoptosis rate were increased, the expression of cleaved caspase-3 and ERK1/2 was up-regulated, and the Bcl-2/Bax ratio was decreased in H, CO, PCO and P groups (P<0.05). Compared with group H, the escape latency was significantly shortened, the hippocampal CO content was increased, and the apoptosis rate was decreased, the cleaved caspase-3 expression was down-regulated, p-ERK1/2 expression was up-regulated, and Bcl-2/Bax ratio was increased in group CO, and the escape latency was significantly prolonged, the hippocampal CO content was decreased, the apoptosis rate was increased, the cleaved caspase-3 expression was up-regulated, p-ERK1/2 expression was down-regulated, and Bcl-2/Bax ratio was decreased in group P (P<0.05). Compared with group CO, the escape latency was significantly prolonged, the apoptosis rate was increased, the cleaved caspase-3 expression was up-regulated, p-ERK1/2 expression was down-regulated, and Bcl-2/Bax ratio was decreased in group PCO (P<0.05). Conclusion The mechanism by which exogenous CO improves cognitive function is related to raising the phosphorylation of ERK1/2 in hippocampal neurons and inhibiting neuronal apoptosis in a rat model of hemorrhage shock and resuscitation. Key words: Extracellular signal-regulated MAP kinases; Carbon monoxide; Reperfusion injury; Hippocampus; Apoptosis; Cognition disorders

Young Blood Plasma Administration to Fight Alzheimer's Disease?

Despite decades of intensive research, no drugs can cure or even stabilize Alzheimer's disease (AD). Current pharmacological treatments only partially mask the symptoms while the disease progresses within the brain. Finding a preventive measure or a cure for people with AD is indeed a worldwide urgent priority. A recent interesting study by T. Wyss-Coray's research group provides the first evidence that exposure to young blood or plasma can reverse some AD-related molecular and behavioral alterations. Heterochronic parabiosis (shared blood circulation) of AD transgenic mice with young healthy mice did not reduce amyloidosis and microglial activation in AD mice, but reversed the loss of synaptophysin and calbindin (critical synaptic proteins, indicators of cognitive decline in AD) in the dentate gyrus, and the abnormal expression, in the hippocampus, of many genes involved in key neuronal signaling pathways. Moreover, repeated intravenous administration of plasma from young healthy mice to AD mice reversed the excessive phosphorylation of hippocampal extracellular signal-regulated kinase (ERK), and improved spatial working memory and associative memory. Although observations in mouse models of AD might not necessarily extrapolate to humans, this preclinical study provides the first demonstration that young plasma has potential therapeutic properties, by ameliorating aspects of the disease that are present in AD patients. Clinical trials are already under way. If young plasma transfusion will be effective in AD patients, it will be important to identify the key factors responsible for the positive effects, as they might lead to the development of molecule interventions with a better efficacy/risk profile.

P.1.j.032 - Perinatal administration of caffeine in mice affects the cognition and spatial memory later in adult life

Caffeine, one of the most widely consumed psychoactive substance in the world, has been shown to affect mood, memory, alertness, and cognitive performance. This study aimed to assess the effect of sub-chronic oral gavage of caffeine on memory and the phosphorylation levels of hippocampal Akt (protein kinase B), GSK-3β (Glycogen Synthase Kinase-3beta) and ERK (extracellular signal-regulated kinase) in mice. Adult male NMRI mice were administered with caffeine at the doses of 0.25, 0.5, 0.75 and 1.5 mg/kg/oral gavage for 10 days before behavioral assessments. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of Akt, GSK-3β and ERK proteins. The results showed that sub-chronic caffeine ingestion at the dose of 0.5 mg/kg improves memory in mice both in passive avoidance and novel object recognition tasks. Furthermore, this memory enhancing dose of caffeine elevated the ratios of phosphorylated to total contents of hippocampal Akt, GSK-3β and ERK. This study suggests that sub-chronic low dose of caffeine improves memory and increases the phosphorylation of hippocampal Akt, GSK-3β and ERK proteins.

ERK-dependent brain-derived neurotrophic factor regulation by hesperidin in mice exposed to chronic mild stress.

A previous study found that the antidepressant-like effects of ethanolic extracts from Hemerocallis citrina are predominantly related to the flavonoid, hesperidin. The study herein aimed to explore the antidepressant-like mechanism of hesperidin in mice induced by chronic mild stress (CMS). The results indicated that hesperidin reversed the reduction of sucrose preference and the elevation of immobility time in mice induced by CMS. In addition, the increase in serum corticosterone levels and decrease in hippocampal extracellular signal-regulated kinase (ERK) phosphorylation and brain-derived neurotrophic factor (BDNF) levels in CMS mice were also ameliorated by hesperidin treatment. In contrast, improvement by hesperidin was suppressed by pretreatment with ERK inhibitor SL327. Taken together, our findings confirmed the antidepressant-like effect of hesperidin and indicated that hesperidin-induced BDNF up-regulation was mediated in an ERK-dependent manner.

Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior

BackgroundAlthough depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Recent evidence has suggested that sirtuins (SIRTs) play a key role in cognition and synaptic plasticity, yet their role in mood regulation remains controversial. Here, we aimed to investigate whether SIRT function is associated with chronic stress-elicited depression-like behaviors and neuronal atrophy. MethodsWe measured SIRT expression and activity in a mouse model of depression. We injected mice with a SIRT1 activator or inhibitor and measured their depression-like behaviors and dendritic spine morphology. To assess the role of SIRT1 directly, we used a viral-mediated gene transfer to overexpress the wild-type SIRT1 or dominant negative SIRT1 and evaluated their depression-like behaviors. Finally, we examined the role of extracellular signal-regulated protein kinases 1 and 2, a potential downstream target of SIRT1, in depression-like behavior. ResultsWe found that chronic stress reduced SIRT1 activity in the dentate gyrus of the hippocampus. Pharmacologic and genetic inhibition of hippocampal SIRT1 function led to an increase in depression-like behaviors. Conversely, SIRT1 activation blocked both the development of depression-related phenotypes and aberrant dendritic structures elicited by chronic stress exposure. Furthermore, hippocampal SIRT1 activation increased the phosphorylation level of extracellular signal-regulated protein kinases 1 and 2 in the stressed condition, and viral-mediated activation and inhibition of hippocampal extracellular signal-regulated protein kinase 2 led to antidepressive and prodepressive behaviors, respectively. ConclusionsOur results suggest that the hippocampal SIRT1 pathway contributes to the chronic stress-elicited depression-related phenotype and aberrant dendritic atrophy.

Role of hippocampal β-adrenergic and glucocorticoid receptors in the novelty-induced enhancement of fear extinction.

Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction.

Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress

Accumulating evidence suggests that cognitive processes, such as learning and memory, are affected in depression and antidepressant treatment may ameliorate cognitive impairments. Recent studies have shown that curcumin exhibits antidepressant-like effects. The aim of the present study was to determine whether curcumin administration influences chronic unpredictable stress (CUS)-induced cognitive deficits and explores underlying mechanisms. Male Wistar rats were subjected to CUS protocol for a period of 5 weeks to induce depression. The depressive-like behavior was tested using sucrose preference test, open field test and Morris water maze test. Effects of curcumin on brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) levels in the hippocampus were also examined. Chronic treatment with curcumin significantly reversed the CUS-induced behavioral and cognitive parameters (reduced sucrose preference and impaired learning and memory function) in stressed rats. Additionally, CUS reduced hippocampal BDNF and ERK levels, while curcumin effectively reversed these alterations. Taken together, our results indicate that the antidepressant-like effects of curcumin in CUS rats are related to its aptitude to promote BDNF and ERK in the hippocampus.

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17β-estradiol (E(2)) is dependent on mTOR signaling in the dorsal hippocampus, and whether E(2)-induced mTOR signaling is dependent on dorsal hippocampal phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) activation. We first demonstrated that the enhancement of object recognition induced by E(2) was blocked by dorsal hippocampal inhibition of ERK, PI3K, or mTOR activation. We then showed that an increase in dorsal hippocampal ERK phosphorylation 5 min after intracerebroventricular (ICV) E(2) infusion was also blocked by dorsal hippocampal infusion of the three cell signaling inhibitors. Next, we found that ICV infusion of E(2) increased phosphorylation of the downstream mTOR targets S6K (Thr-421) and 4E-BP1 in the dorsal hippocampus 5 min after infusion, and that this phosphorylation was blocked by dorsal hippocampal infusion of inhibitors of ERK, PI3K, and mTOR. Collectively, these data demonstrate for the first time that activation of the dorsal hippocampal mTOR signaling pathway is necessary for E(2) to enhance object recognition memory consolidation and that E(2)-induced mTOR activation is dependent on upstream activation of ERK and PI3K signaling.

The Effects of Reboxetine Treatment on Depression-like Behavior, Brain Neurotrophins, and ERK Expression in Rats Exposed to Chronic Mild Stress

Chronic mild stress (CMS) in rats is an established rodent depression model. Antidepressants attenuate the depression-like symptoms and prevent the biochemical changes caused by stress. In the present study, we examined the effect of CMS and the selective norepinephrine reuptake inhibitor (NRI) reboxetine (REB) treatment on behavioral parameters in rats and on hippocampal and cortical neurotrophic factors. Male Sprague Dawley rats were exposed for 5 weeks to a variety of mild stressors. REB (5 mg/kg/i.p.) was daily injected to half of the stressed and unstressed groups. Animal behavior following CMS was tested using the Morris Water Maze (MWM) cognitive paradigm and by monitoring sucrose intake and weight gain. After 5 weeks of CMS, stressed rats showed decreased sucrose intake, and REB treatment normalized this decrease. CMS reduced hippocampal brain-derived neurotrophic factor (BDNF) levels, and REB treatment reversed this alteration and increased BDNF receptor (TrkB) levels. REB elevated hippocampal extracellular signal-regulated kinase (ERK) phosphorylation of both stressed and unstressed rats. In conclusion, our study shows that BDNF, its receptor TrkB, and ERK participate in the neurobiological response to chronic stress and in the molecular and cellular activities of REB in the hippocampus.

The progesterone-induced enhancement of object recognition memory consolidation involves activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways in the dorsal hippocampus

Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17β-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory consolidation in young ovariectomized female mice (Orr et al., 2009). The goal of the present study was to identify the biochemical alterations that might underlie this mnemonic enhancement. We hypothesized that the P-induced enhancement of object recognition would be dependent on activation of the ERK and mTOR pathways. In young ovariectomized mice, we found that bilateral dorsal hippocampal infusion of P significantly increased levels of phospho-p42 ERK and the mTOR substrate S6K in the dorsal hippocampus 5min after infusion. Phospho-p42 ERK levels were downregulated 15min after infusion and returned to baseline 30min after infusion, suggesting a biphasic effect of P on ERK activation. Dorsal hippocampal ERK and mTOR activation were necessary for P to facilitate memory consolidation, as suggested by the fact that inhibitors of both pathways infused into the dorsal hippocampus immediately after training blocked the P-induced enhancement of object recognition. Collectively, these data provide the first demonstration that the ability of P to enhance memory consolidation depends on the rapid activation of cell signaling and protein synthesis pathways in the dorsal hippocampus.

Hippocampal Extracellular Signal-Regulated Kinase Signaling has a Role in Passive Avoidance Memory Retrieval Induced by GABAA Receptor Modulation in Mice

Available evidence strongly suggests that the γ-aminobutyric acid type A (GABA(A)) receptor has a crucial role in memory retrieval. However, the signaling mechanisms underlying the role of GABA(A) receptor modulation in memory retrieval are unclear. We conducted one-trial passive avoidance task with pre-retention trial drug administration in the hippocampus to test the effects of GABA(A) receptor modulation on memory retrieval. We further tested the co-involvement of signaling molecules: extracellular signal-regulated kinase (ERK), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and cAMP responsive element-binding protein (CREB). First, we observed that the phosphorylation of hippocampal ERK was required for memory retrieval during the task. Accordingly, to investigate whether GABA(A) receptor activation or inhibition induces ERK phosphorylation during memory retrieval, drugs that target the GABA(A) receptor were administered into the hippocampus before the retention trial. Muscimol, a GABA(A) receptor agonist, and diazepam, an agonist to benzodiazepine-binding site of GABA(A) receptor, blocked retention trial-induced ERK phosphorylation and impaired memory retrieval. Furthermore, co-treatment with sub-effective dose of U0126, a mitogen-activated protein kinase inhibitor, blocked the upregulation of ERK phosphorylation and impaired memory retrieval, and bicuculline methiodide (BMI), a GABA(A) receptor antagonist, increased ERK phosphorylation induced by the retention trial and facilitated memory retrieval. Finally, the effects of BMI were blocked by the co-application of a sub-effective dose of U0126. These results suggest that GABA(A) receptor-mediated memory retrieval is closely related to ERK activity.

Estradiol-Induced Object Memory Consolidation in Middle-Aged Female Mice Requires Dorsal Hippocampal Extracellular Signal-Regulated Kinase and Phosphatidylinositol 3-Kinase Activation

We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17beta-estradiol (E(2)) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E(2) has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular or intrahippocampal E(2) infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E(2)-induced enhancement in middle-aged females was blocked by intrahippocampal inhibition of ERK or PI3K activation. Intrahippocampal or intracerebroventricular E(2) infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15 min, but not 5 min, after infusion, an effect that was blocked by intrahippocampal inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after intrahippocampal or intracerebroventricular E(2) infusion in middle-aged, but not aged, females. Intracerebroventricular E(2) infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by intrahippocampal PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/Akt and ERK signaling pathways is necessary for E(2) to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E(2)-induced object recognition memory enhancement in young and middle-aged females and that the inability of E(2) to activate these pathways may underlie its failure to enhance object recognition in aged females.

Developmental iodine deficiency resulting in hypothyroidism reduces hippocampal ERK1/2 and CREB in lactational and adolescent rats

BackgroundDevelopmental iodine deficiency (ID) leads to inadequate thyroid hormone that impairs learning and memory with an unclear mechanism. Here, we show that hippocampal extracellular signal-regulated kinase (ERK1/2) and cAMP response element-binding protein (CREB) are implicated in the impaired learning and memory in lactational and adolescent rat hippocampus following developmental ID and hypothyroidism.MethodsThree developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 ppm or 15 ppm)-added drinking water from gestational day (GD) 6 till postnatal day (PN) 28. Then, the total and phorsporylated ERK1/2 and total and phorsporylated CREB in the hippocampus were detected with western blot on PN14, PN21, PN28 and PN42.ResultsThe iodine-deficient and hypothyroid pups showed lower serum FT3 and FT4 levels, smaller body size, and delayed eyes opening. The mean number of surviving cells in the hippocampus of the iodine-deficient and 15 ppm PTU-treated rats was significantly reduced compared to controls (P < 0.05). Iodine-deficient and 15 ppm PTU-treatment groups demonstrated significantly lower level of total and phosphorylated ERK1/2 and CREB than the controls on PN14, PN21 and PN28 (P < 0.05, respectively). The reduction of ERK1/2 and CREB was not reversible with the restoration of serum thyroid hormone concentrations on PN42.ConclusionsDevelopmental ID and hypothyroidism down-regulate hippocampal ERK1/2 and CREB in lactational and adolescent rats.